Switching from inotersen to eplontersen in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: analysis from NEURO-TTRansform.

BACKGROUND: The phase 3 NEURO-TTRansform trial showed eplontersen treatment for 65 weeks reduced transthyretin (TTR), halted progression of neuropathy impairment, and improved quality of life (QoL) in adult patients with hereditary TTR-mediated amyloidosis with polyneuropathy (ATTRv-PN), vs. historical placebo. METHODS: NEURO-TTRansform enrolled patients with ATTRv-PN. A subset of patients were randomized to receive subcutaneous inotersen 300 mg weekly (Weeks 1-34) and subsequently switched to subcutaneous eplontersen 45 mg every 4 weeks (Weeks 37-81). Change in serum TTR and treatment-emergent adverse events (TEAEs) were evaluated through Week 85. Effects on neuropathy impairment, QoL, and nutritional status were also evaluated. RESULTS: Of 24 patients randomized to inotersen, 20 (83%) switched to eplontersen at Week 37 and four discontinued due to AEs/investigator decision. Absolute change in serum TTR was greater after switching from inotersen (-74.3%; Week 35) to eplontersen (-80.6%; Week 85). From the end of inotersen treatment, neuropathy impairment and QoL were stable (i.e., did not progress) while on eplontersen, and there was no deterioration in nutritional status. TEAEs were fewer with eplontersen (Weeks 37-85; 19/20 [95%] patients) compared with inotersen (up to Week 35; 24/24 [100%] patients). Mean platelet counts decreased during inotersen treatment (mean nadir reduction ‒40.7%) and returned to baseline during eplontersen treatment (mean nadir reduction, ‒3.2%). CONCLUSIONS: Switching from inotersen to eplontersen further reduced serum TTR, halted disease progression, stabilized QoL, restored platelet count, and improved tolerability, without deterioration in nutritional status. This supports a positive benefit-risk profile for patients with ATTRv-PN who switch from inotersen to eplontersen.

Strategies, Facilitators, and Barriers in Managing Academic Occupational Disruptions: Implications for Occupational Therapy Education.

Background: Higher education was gravely affected by the pandemic which caused academic occupational disruptions and affected students. Challenges in successful engagement in occupations influence the health and well-being of the individual. Consequently, it is vital for occupational therapist (OT) educators to be informed on how to manage academic occupational disruptions to minimize its occurrence, mitigate its impact, and support students' academic occupations. Objectives: This study aimed to determine the strategies, facilitators, and barriers in managing academic occupational disruptions encountered by Filipino OT educators. Methods: Respondents were ninety (90) Filipino OT educators coming from the different HEIs in the Philippines offering BSOT who completed an online cross-sectional survey. A 4-point Likert-scale was used to determine the strategies, facilitators, and barriers in managing academic occupational disruptions. Descriptive statistics was used for data analysis. Results: Respondents often (M = 2.95, SD = 0.94) utilize strategies for managing academic occupational disruptions, highlighting scheduling of synchronous and asynchronous sessions to balance online workload as the most utilized strategy. Respondents often (M = 3.00, SD = 0.70) encounter facilitators of managing academic occupational disruptions, citing flexibility of the school in adapting existing courses based on the context of delivery as the most common facilitator. Respondents sometimes (M = 2.19, SD = 0.95) encounter barriers to managing academic occupational disruptions, indicating need to work for income as the top barrier. Conclusion: Despite the utilization of strategies and presence of facilitators in managing academic occupational disruptions, Filipino OT educators still encountered barriers. Psychosocial support and needs were also highlighted across strategies, facilitators, and barriers in managing academic occupational disruptions. This prompts for further sustainable development of OT competence to inform occupational therapy educators on how to minimize academic occupational disruptions, to mitigate its impact, and to support students' academic occupations.

Mediation of antitumor activity by AZD4820 oncolytic vaccinia virus encoding IL-12.

Oncolytic viruses are engineered to selectively kill tumor cells and have demonstrated promising results in early-phase clinical trials. To further modulate the innate and adaptive immune system, we generated AZD4820, a vaccinia virus engineered to express interleukin-12 (IL-12), a potent cytokine involved in the activation of natural killer (NK) and T cells and the reprogramming of the tumor immune microenvironment. Testing in cultured human tumor cell lines demonstrated broad in vitro oncolytic activity and IL-12 transgene expression. A surrogate virus expressing murine IL-12 demonstrated antitumor activity in both MC38 and CT26 mouse syngeneic tumor models that responded poorly to immune checkpoint inhibition. In both models, AZD4820 significantly upregulated interferon-gamma (IFN-γ) relative to control mice treated with oncolytic vaccinia virus (VACV)-luciferase. In the CT26 study, 6 of 10 mice had a complete response after treatment with AZD4820 murine surrogate, whereas control VACV-luciferase-treated mice had 0 of 10 complete responders. AZD4820 treatment combined with anti-PD-L1 blocking antibody augmented tumor-specific T cell immunity relative to monotherapies. These findings suggest that vaccinia virus delivery of IL-12, combined with immune checkpoint blockade, elicits antitumor immunity in tumors that respond poorly to immune checkpoint inhibitors.

Developmental basis of SHH medulloblastoma heterogeneity.

Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different developmental stages. Additionally, using multiplexed proteomic imaging and MALDI imaging mass spectrometry, we identify distinct histological and metabolic profiles for highly differentiated tumors. Our approaches are applicable to understanding the interplay between heterogeneity and differentiation in other cancers and can provide important insights for the design of targeted therapies.

A qualitative exploration on the role of occupational therapy in mental health and psychosocial support for students in the university setting in the Philippines

Background@#Occupational therapy (OT) can be part of mental health and psychosocial support (MHPSS) in the university setting. Numerous studies worldwide have highlighted the negative impact of COVID-19 on mental health due to isolation and restrictions. In the Philippines, these issues were exacerbated among students, whose abrupt shift to remote learning negatively affected their mental well-being. As universities reopened, there is an opportunity for OT to support students' mental health. @*Objectives@#This study presents the findings of an online group discussion and an online forum that explored the role of OT in MHPSS in the Philippine university setting. Moreover, this study aimed to (1) describe the perceptions of Filipino OT practitioners (OTPs) on their role in the university setting, and (2) describe thoughts of Filipino OTPs on being part of MHPSS services. @*Method@#Using a qualitative exploratory design, data was gathered through an online discussion and an online forum. Thirty-five Filipino OTPs with a background in mental health practice served as the participants. Data was analysed using constant comparison.@*Results@#Analyses of data generated four themes: (1) awareness of the importance of MHPSS as student support, (2) mental health and occupation-focused support in the education setting, (3) role of OT in MHPSS, and (4) potential for interprofessional services. @*Conclusion@#Need for OT in MHPSS is justified by rising issues in anxiety, depression, trauma, and stress that can be addressed using an occupation-focused approach. OTPs can provide non-specialized services like PFA, or specialized individual or group-based interventions. However, OTPs think that they need to know more about MHPSS to contribute across all levels of MHPSS.

Strategies, facilitators, and barriers in managing academic occupational disruptions: Implications for occupational therapy education

Background@#Higher education was gravely affected by the pandemic which caused academic occupational disruptions and affected students. Challenges in successful engagement in occupations influence the health and well-being of the individual. Consequently, it is vital for occupational therapist (OT) educators to be informed on how to manage academic occupational disruptions to minimize its occurrence, mitigate its impact, and support students’ academic occupations.@*Objectives@#This study aimed to determine the strategies, facilitators, and barriers in managing academic occupational disruptions encountered by Filipino OT educators.@*Methods@#Respondents were ninety (90) Filipino OT educators coming from the different HEIs in the Philippines offering BSOT who completed an online cross-sectional survey. A 4-point Likert-scale was used to determine the strategies, facilitators, and barriers in managing academic occupational disruptions. Descriptive statistics was used for data analysis.@*Results@#Respondents often (M = 2.95, SD = 0.94) utilize strategies for managing academic occupational disruptions, highlighting scheduling of synchronous and asynchronous sessions to balance online workload as the most utilized strategy. Respondents often (M = 3.00, SD = 0.70) encounter facilitators of managing academic occupational disruptions, citing flexibility of the school in adapting existing courses based on the context of delivery as the most common facilitator. Respondents sometimes (M = 2.19, SD = 0.95) encounter barriers to managing academic occupational disruptions, indicating need to work for income as the top barrier.@*Conclusion@#Despite the utilization of strategies and presence of facilitators in managing academic occupational disruptions, Filipino OT educators still encountered barriers. Psychosocial support and needs were also highlighted across strategies, facilitators, and barriers in managing academic occupational disruptions. This prompts for further sustainable development of OT competence to inform occupational therapy educators on how to minimize academic occupational disruptions, to mitigate its impact, and to support students’ academic occupations.

Acidic Methanol Treatment Facilitates Matrix-Assisted Laser Desorption Ionization-Mass Spectrometry Imaging of Energy Metabolism.

Detection of small molecule metabolites (SMM), particularly those involved in energy metabolism using MALDI-mass spectrometry imaging (MSI), is challenging due to factors including ion suppression from other analytes present (e.g., proteins and lipids). One potential solution to enhance SMM detection is to remove analytes that cause ion suppression from tissue sections before matrix deposition through solvent washes. Here, we systematically investigated solvent treatment conditions to improve SMM signal and preserve metabolite localization. Washing with acidic methanol significantly enhances the detection of phosphate-containing metabolites involved in energy metabolism. The improved detection is due to removing lipids and highly polar metabolites that cause ion suppression and denaturing proteins that release bound phosphate-containing metabolites. Stable isotope infusions of [13C6]nicotinamide coupled to MALDI-MSI ("Iso-imaging") in the kidney reveal patterns that indicate blood vessels, medulla, outer stripe, and cortex. We also observed different ATP:ADP raw signals across mouse kidney regions, consistent with regional differences in glucose metabolism favoring either gluconeogenesis or glycolysis. In mouse muscle, Iso-imaging using [13C6]glucose shows high glycolytic flux from infused circulating glucose in type 1 and 2a fibers (soleus) and relatively lower glycolytic flux in type 2b fiber type (gastrocnemius). Thus, improved detection of phosphate-containing metabolites due to acidic methanol treatment combined with isotope tracing provides an improved way to probe energy metabolism with spatial resolution in vivo.

Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy.

Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group. Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

Natural aging and Alzheimer's disease pathology increase susceptibility to focused ultrasound-induced blood-brain barrier opening.

Focused Ultrasound (FUS) paired with systemically-injected microbubbles (µB) is capable of transiently opening the blood-brain barrier (BBBO) for noninvasive and targeted drug delivery to the brain. FUS-BBBO is also capable of modulating the neuroimmune system, further qualifying its therapeutic potential for neurodegenerative diseases like Alzheimer's disease (AD). Natural aging and AD impose significant strain on the brain and particularly the BBB, modifying its structure and subsequently, its functionality. The emerging focus on treating neurodegenerative diseases with FUS-BBBO necessitates an investigation into the extent that age and AD affect the BBB's response to FUS. FUS-BBBO was performed with a 1.5-MHz, geometrically focused transducer operated at 450 kPa and paired with a bolus microbubble injection of 8 × 108 µB/mL. Here we quantify the BBBO, BBB closing (BBBC) timeline, and BBB permeability (BBBP) following FUS-BBBO in male mice with and without AD pathology, aged 10 weeks, one year, or two years. The data presented herein indicates that natural aging and AD pathology may increase initial BBBO volume by up to 34.4% and 40.7% respectively, extend BBBC timeline by up to 1.3 and 1.5 days respectively, and increase BBBP as measured by average Ktrans values up to 80% and 86.1% respectively in male mice. This characterization of the BBB response to FUS-BBBO with age and AD further clarifies the nature and extent of the functional impact of these factors and may offer new considerations for planning FUS-BBBO interventions in aged and AD populations.

Slow TCA flux and ATP production in primary solid tumours but not metastases.

Tissues derive ATP from two pathways-glycolysis and the tricarboxylic acid (TCA) cycle coupled to the electron transport chain. Most energy in mammals is produced via TCA metabolism1. In tumours, however, the absolute rates of these pathways remain unclear. Here we optimize tracer infusion approaches to measure the rates of glycolysis and the TCA cycle in healthy mouse tissues, Kras-mutant solid tumours, metastases and leukaemia. Then, given the rates of these two pathways, we calculate total ATP synthesis rates. We find that TCA cycle flux is suppressed in all five primary solid tumour models examined and is increased in lung metastases of breast cancer relative to primary orthotopic tumours. As expected, glycolysis flux is increased in tumours compared with healthy tissues (the Warburg effect2,3), but this increase is insufficient to compensate for low TCA flux in terms of ATP production. Thus, instead of being hypermetabolic, as commonly assumed, solid tumours generally produce ATP at a slower than normal rate. In mouse pancreatic cancer, this is accommodated by the downregulation of protein synthesis, one of this tissue's major energy costs. We propose that, as solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.

Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen.

INTRODUCTION: Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin (TTR) amyloid fibrils. ATTRv amyloidosis occurs in both males and females. Eplontersen (ION-682884), a ligand-conjugated antisense oligonucleotide designed to degrade hepatic TTR mRNA, is being evaluated for the treatment of ATTRv amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, multicenter, open-label NEURO-TTRansform study (NCT04136184). To describe the study population of this pivotal trial, here we report the baseline characteristics of patients enrolled in the NEURO-TTRansform study. METHODS: Patients eligible for NEURO-TTRansform were 18-82 years old with a diagnosis of ATTRv-PN and Coutinho stage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance) disease; documented TTR gene variant; signs and symptoms consistent with neuropathy associated with ATTRv; no prior liver transplant; and New York Heart Association (NYHA) functional class I or II. RESULTS: The NEURO-TTRansform study enrolled 168 patients across 15 countries/territories (North America, 15.5%; Europe, 38.1%; South America/Australia/Asia, 46.4%). At baseline, the study cohort had a mean age of 52.8 years, 69.0% of patients were male, and 78.0% of patients were White. The V30M variant was most prevalent (60.1% of patients), and prevalence varied by region. Overall, 56.5% and 17.3% of patients had received previous treatment with tafamidis or diflunisal, respectively. A majority of patients (79.2%) had Coutinho stage 1 disease (unimpaired ambulation) and early (before age 50) disease onset (53.0%). Time from diagnosis to enrollment was 46.6 (57.4) months (mean [standard deviation]). Most patients had a baseline polyneuropathy disability (PND) score of I (40.5%) or II (41.1%), and the mean modified Neuropathy Impairment Score + 7 (mNIS + 7) was 79.0. CONCLUSION: The recruited population in the ongoing NEURO-TTRansform study has global representation characteristic of contemporary clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04136184.

Hereditary transthyretin amyloidosis, also called ATTRv amyloidosis, is a rare and serious disease that is passed down within families. People with ATTRv amyloidosis have a genetic variant that causes their liver to make abnormal versions of the transthyretin protein (also known as "TTR"), which clump together into "clusters" called amyloids. The amyloid clusters build up in various body tissues and organs such as the liver, nerves, heart, and kidney, causing damage that could ultimately lead to death. ATTRv amyloidosis is a progressive disease, meaning that it gets worse over time. Liver transplant has traditionally been the only treatment option. Recently, drugs that target TTR have been approved by the FDA, and potential drugs are being tested in clinical trials. Eplontersen is designed to degrade TTR mRNA in the liver and inhibit the production of TTR protein. NEURO-TTRansform is a global phase 3 study investigating the effectiveness and safety of eplontersen in 168 adults with ATTRv amyloidosis with polyneuropathy (ATTRv-PN), a disease in which amyloid accumulation in peripheral nerves causes multisystem damage and eventually death. This scientific article describes the characteristics of the patients at enrollment, including age, gender, geographic location, and disease-related information, to help improve the understanding of ATTRv-PN. NEURO-TTRansform is an ongoing study, and the results will be published at a later time as prespecified in the analysis plan.

What can we learn from 28 years of monitoring of fish tissue polychlorinated biphenyls in Michigan's rivers?

Polychlorinated biphenyls (PCBs) are an important part of chemical legacies in the Laurentian Great Lakes basin. Used in industrial products worldwide, PCBs are now extensively monitored because of their potential toxicity to humans. Fish consumption is a major pathway for exposure. Edible portion (i.e., fish fillet) data from Michigan's fish tissue PCB monitoring program were evaluated using regression statistics, principal component analysis, and t-tests to answer three questions: (1) How do fish tissue total PCB concentrations vary across Michigan's rivers? (2) Are the PCB congener patterns uniformly distributed among tested sites and species? (3) Do monitoring methods limit our ability to discern trends in fish tissue PCB concentrations? Our results indicate that although contaminated sites have been successfully identified, based on higher PCB concentrations in samples from Areas of Concern (AOCs) compared to non-AOC sites, 77% of fish samples from 2010 to 2015 exceeded the safe fish tissue PCB concentration for unrestricted consumption (97 g/day) by sensitive populations. The PCB congener profiles vary among species and locations. Results demonstrate that these data are not useful for supplementing ongoing spatial and temporal trend analysis. Only 15 of the 83 species + waterbody pairs had adequate data for evaluating temporal trends with more than three data points. In general, the trends at each location varied based on the analytical method. Conclusions from this work can inform revisions to existing monitoring programs and improve our ability to protect human health. Integr Environ Assess Manag 2023;19:152-162. © 2022 SETAC.

Reintegration of returning migrant healthcare workers into the Philippine workforce: A qualitative case study

AIM@#This study aims to explore the reintegration experiences of returning migrant healthcare workers in the Philippines.@*BACKGROUND@#Return migration and reintegration of healthcare labor force is a relevant part of the migration process valuable in the improvement of human capital in source countries through transfer of knowledge and skills. However, this research field has received little attention in terms of policy, program, and research development. Hence, there is a paucity of information in the Philippines describing the reintegration experiences of returning migrant healthcare workers despite its maturity in health worker migration.@*METHODS@# A qualitative case study approach was utilized in this study. Initially, an online literature review of electronic databases and grey literature regarding reintegration of migrant workers in the Philippines was performed. This was followed by online in- depth interviews among purposively selected potential, current, or returning nurses, rehabilitation therapists, and caregiver health worker migrants through Zoom web conferencing platform. Government, private, and non-government institutions involved in the migration of health workers were also invited to participate in online focus group discussions and key informant interviews. An inductive content analysis using matrices was utilized to determine relevant descriptive codes, categories, and themes.@*RESULTS@#Return migration and reintegration is perceived as an uncommon phenomenon among healthcare worker migrants. Nonetheless, motivations and grounds of opting to return and reintegrate in the Philippines can mostly be due to personal reasons or entrepreneurial aspirations. Upon return, they successfully held teaching and training positions, engaged in business through specialized clinics, or established professional associations. There was largely a perceived lack of awareness of government efforts on reintegration as it was felt that services and assistance were limited. Further observed restraints to return migration include lower wages in the Philippines, lack of knowledge on financial management, paucity of skills and qualifications recognition acquired overseas in their home country, and absence of professional network support. The COVID-19 pandemic also positively or negatively influenced healthcare worker migration.@*CONCLUSION@#This study highlighted the motivations and restraints of health worker migrants in returning to reintegrate in the Philippines. The availability and deficiency in policies, programs, and services for returning migrant workers were also emphasized. In addition, the aspects and prospects of return migration and reintegration, as well as the challenges posed by the COVID-19 pandemic on healthcare worker reintegration was identified. The Philippine government and other concerned agencies need to ensure a supportive environment that will foster a positively conducive reintegration experience for returning healthcare worker migrants.

Making inroads to precision medicine for the treatment of autoimmune diseases: Harnessing genomic studies to better diagnose and treat complex disorders.

Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body's natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics.

Care of Patients With Transthyretin Amyloidosis: the Roles of Nutrition, Supplements, Exercise, and Mental Health.

Transthyretin (ATTR) amyloidosis is a debilitating disease that results in organ failure and eventual death. As the disease progresses, patients experience neurologic, gastrointestinal, and cardiovascular symptoms that increasingly compromise their nutritional status and exercise capacity. These symptoms cause considerable emotional stress and mental health challenges for patients and caregivers. This review summarizes common symptoms and mechanisms associated with malnutrition and exercise intolerance, and sources of emotional stress, and offers therapeutic strategies to address these issues. Although earlier diagnosis and disease-specific treatment are central to caring for patients with ATTR amyloidosis, additional attention to symptom-focused treatments to improve nutritional status, maintain exercise tolerance and capacity, and improve and maintain mental health are also important. In conclusion, a team-based approach involving multiple clinicians and providers can offer more comprehensive and coordinated care, support, and education for patients and caregivers.

COVID-19 Transmission to Health Care Personnel During Tracheostomy Under a Multidisciplinary Safety Protocol.

BACKGROUND: Tracheostomies are highly aerosolizing procedures yet are often indicated in patients with COVID-19 who require prolonged intubation. Robust investigations of the safety of tracheostomy protocols and provider adherence and evaluations are limited. OBJECTIVES: To determine the rate of COVID-19 infection of health care personnel involved in COVID-19 tracheostomies under a multidisciplinary safety protocol and to investigate health care personnel's attitudes and suggested areas for improvement concerning the protocol. METHODS: All health care personnel involved in tracheostomies in COVID-19-positive patients from April 9 through July 11, 2020, were sent a 22-item electronic survey. RESULTS: Among 107 health care personnel (80.5%) who responded to the survey, 5 reported a positive COVID-19 test result (n = 2) or symptoms of COVID-19 (n = 3) within 21 days of the tracheostomy. Respondents reported 100% adherence to use of adequate personal protective equipment. Most (91%) were familiar with the tracheostomy protocol and felt safe (92%) while performing tracheostomy. Suggested improvements included creating dedicated tracheostomy teams and increasing provider choices surrounding personal protective equipment. CONCLUSIONS: Multidisciplinary engagement in the development and implementation of a COVID-19 tracheostomy protocol is associated with acceptable safety for all members of the care team.

Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival.

Autophagy defects are a risk factor for inflammatory bowel diseases (IBDs) through unknown mechanisms. Whole-body conditional deletion of autophagy-related gene (Atg) Atg7 in adult mice (Atg7Δ/Δ) causes tissue damage and death within 3 mo due to neurodegeneration without substantial effect on intestine. In contrast, we report here that whole-body conditional deletion of other essential Atg genes Atg5 or Fip200/Atg17 in adult mice (Atg5Δ/Δ or Fip200Δ/Δ) caused death within 5 d due to rapid autophagy inhibition, elimination of ileum stem cells, and loss of barrier function. Atg5Δ/Δ mice lost PDGFRα+ mesenchymal cells (PMCs) and Wnt signaling essential for stem cell renewal, which were partially rescued by exogenous Wnt. Matrix-assisted laser desorption ionization coupled to mass spectrometry imaging (MALDI-MSI) of Atg5Δ/Δ ileum revealed depletion of aspartate and nucleotides, consistent with metabolic insufficiency underlying PMC loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss, as deletion of Atg5 more gradually extended lifespan phenocopying deletion of Atg7 or Atg12. Thus, autophagy is required for PMC metabolism and ileum stem cell and mammalian survival. Failure to maintain PMCs through autophagy may therefore contribute to IBD.

Translational Activation of ATF4 through Mitochondrial Anaplerotic Metabolic Pathways Is Required for DLBCL Growth and Survival.

Diffuse large B-cell lymphomas (DLBCL) are broadly dependent on anaplerotic metabolism regulated by mitochondrial SIRT3. Herein we find that translational upregulation of ATF4 is coupled with anaplerotic metabolism in DLBCLs due to nutrient deprivation caused by SIRT3 driving rapid flux of glutamine into the tricarboxylic acid (TCA) cycle. SIRT3 depletion led to ATF4 downregulation and cell death, which was rescued by ectopic ATF4 expression. Mechanistically, ATF4 translation is inhibited in SIRT3-deficient cells due to the increased pools of amino acids derived from compensatory autophagy and decreased glutamine consumption by the TCA cycle. Absence of ATF4 further aggravates this state through downregulation of its target genes, including genes for amino acid biosynthesis and import. Collectively, we identify a SIRT3-ATF4 axis required to maintain survival of DLBCL cells by enabling them to optimize amino acid uptake and utilization. Targeting ATF4 translation can potentiate the cytotoxic effect of SIRT3 inhibitor to DLBCL cells. SIGNIFICANCE: We discovered the link between SIRT3 and ATF4 in DLBCL cells, which connected lymphoma amino acid metabolism with ATF4 translation via metabolic stress signals. SIRT3-ATF4 axis is required in DLBCL cells regardless of subtype, which indicates a common metabolic vulnerability in DLBCLs and can serve as a therapeutic target.This article is highlighted in the In This Issue feature, p. 1.

True Saccular Aneurysm at the Iliac Bifurcation in an Adolescent: Case Report and Review of Lower Limb Vascular Embryology.

INTRODUCTION: Isolated iliac artery aneurysms are an uncommon occurrence in the absence of concurrent aortic disease in the adult population and are a rare entity in children and adolescents. Paediatric patients may present with false aneurysms less frequently but true aneurysms are exceptional. In this report, the case of an iliac bifurcation true saccular aneurysm is described. REPORT: An 18 year old woman without history of infection, trauma, connective tissue disorders, or vasculitis, was referred with an incidental left iliac bifurcation saccular aneurysm. She underwent open surgical resection of the aneurysm with primary re-anastomosis of the common to external iliac arteries and ligation of the internal iliac artery. Histopathological assessment did not show any inflammatory or other underlying disease process. DISCUSSION: A case is presented of an isolated iliac bifurcation true aneurysm in an adolescent and its successful treatment. It is plausible that incomplete involution of the embryologically dominant sciatic artery may have been the cause for this presentation and for other congenital iliac artery aneurysms. Literature review of other paediatric iliac aneurysms shows an array of postulated underlying causes and treatment strategies.

High TB burden and low notification rates in the Philippines: The 2016 national TB prevalence survey.

SETTING: The 3rd national tuberculosis (TB) survey in the Philippines in 2007 reported a significant decline in the prevalence of TB. Since then, more significant investments for TB control have been made, yet TB burden estimates from routine surveillance data remain relatively stable. OBJECTIVE: To estimate the prevalence of bacteriologically confirmed pulmonary TB in the Philippines amongst individuals aged ≥15 years in 2016. DESIGN: In March-December 2016, we conducted a population-based survey with stratified, multi-stage cluster sampling of residents in 106 clusters aged ≥15 years. Survey participants were screened for TB by symptom-based interview and digital chest X-ray. Those with cough ≥2 weeks and/or haemoptysis and/or chest X-ray suggestive of TB were requested to submit 2 sputum specimens for Xpert MTB/RIF, direct sputum smear microscopy using LED fluorescent microscopy, and mycobacterial solid culture (Ogawa method). Bacteriologically confirmed pulmonary TB was defined as MTB culture positive and/or Xpert positive. RESULTS: There were 46,689 individuals interviewed, and 41,444 (88.8%) consented to a chest X-ray. There were 18,597 (39.8%) eligible for sputum examination and 16,242 (87.3%) submitted at least one specimen. Out of 16,058 sputum-eligible participants, 183 (1.1%) were smear-positive. There were 466 bacteriologically confirmed TB cases: 238 (51.1%) Xpert positive, 69 (14.8%) culture positive, and 159 (34.1%) positive by both Xpert and culture. The estimated TB prevalence per 100,000 population aged ≥15 years was 434 (95% CI: 350-518) for smear-positive TB, and 1,159 (95% CI: 1,016-1,301) for bacteriologically confirmed TB. CONCLUSION: This nationally representative survey found that the TB burden in the Philippines in 2016 was higher than estimated from routine TB surveillance data. There was no evidence of a decline in smear and culture positive TB from the 2007 survey despite significant investments in TB control. New strategies for case-finding and patient-centered care must be intensified and expanded.